HIF-1α-Deficiency in Myeloid Cells Leads to a Disturbed Accumulation of Myeloid Derived Suppressor Cells (MDSC) During Pregnancy and to an Increased Abortion Rate in Mice
HIF-1α-Deficiency in Myeloid Cells Leads to a Disturbed Accumulation of Myeloid Derived Suppressor Cells (MDSC) During Pregnancy and to an Increased Abortion Rate in Mice
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DOI：
10.3389/fimmu.2019.00161
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发表时间：
2019-02-05
影响因子：
7.3
通讯作者：
Gille, Christian
中科院分区：
文献类型：
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作者：
Koestlin-Gille, Natascha;Dietz, Stefanie;Gille, Christian
堕胎是造成非故意无子女的最重要原因。在怀孕期间，母体免疫细胞与半同种异体胎儿的细胞密切接触。母体免疫系统失调导致对妊娠的适应不良，往往在流产的发病机制中发挥作用。髓源性抑制细胞（MDSC）是抑制其他免疫细胞（特别是T细胞）功能的髓细胞，从而对癌症、败血症或创伤等疾病产生负面影响。然而，它们似乎也是维持母胎耐受性所必需的。调控妊娠期间MDSC扩增和功能的机制还不完全清楚。在肿瘤环境中，缺氧对于MDSC的积累和激活至关重要。缺氧对早期胎盘和胚胎发育也很重要。缺氧的影响是通过缺氧诱导因子1 α（HIF-1 α）介导的。在本研究中，我们的目的是检查骨髓细胞中HIF-1 α在妊娠期间MDSC积累和MDSC功能以及妊娠结局中的作用。因此，我们使用了骨髓细胞中靶向缺失HIF-1 α的小鼠模型（骨髓HIF-KO），并与非妊娠动物和野生型（WT）动物相比，分析了妊娠第10.5天妊娠小鼠的血液、脾脏和子宫。此外，我们通过测定WT和髓系HIF-KO动物的着床失败率和流产率来分析妊娠成功率。我们发现，小鼠中的髓样HIF-KO导致MDSC在妊娠子宫中的积累被消除，并且MDSC的抑制活性受损。虽然MDSC上的趋化因子受体和整合素的表达不受HIF-1 α的影响，但髓样HIF-1 α KO导致子宫中MDSC的凋亡率增加。骨髓-HIF-KO导致阳性阴道栓后非妊娠动物的比例增加和流产率增加，表明MDSC中HIF-1 α依赖性途径的激活对维持妊娠很重要。
Abortions are the most important reason for unintentional childlessness. During pregnancy, maternal immune cells are in close contact to cells of the semi-allogeneic fetus. Dysregulation of the maternal immune system leading to defective adaptation to pregnancy often plays a role in pathogenesis of abortions. Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress functions of other immune cells, especially T-cells, thereby negatively affecting diseases such as cancer, sepsis or trauma. They seem, however, also necessary for maintenance of maternal-fetal tolerance. Mechanisms regulating MDSC expansion and function during pregnancy are only incompletely understood. In tumor environment, hypoxia is crucial for MDSC accumulation and activation. Hypoxia is also important for early placenta and embryo development. Effects of hypoxia are mediated through hypoxia-inducible factor 1 alpha (HIF-1 alpha). In the present study we aimed to examine the role of HIF-1 alpha in myeloid cells for MDSC accumulation and MDSC function during pregnancy and for pregnancy outcome. We therefore used a mouse model with targeted deletion of HIF-1 alpha in myeloid cells (myeloid HIF-KO) and analyzed blood, spleens and uteri of pregnant mice at gestational day E 10.5 in comparison to non-pregnant animals and wildtype (WT) animals. Further we analyzed pregnancy success by determining rates of failed implantation and abortion in WT and myeloid HIF-KO animals. We found that myeloid HIF-KO in mice led to an abrogated MDSC accumulation in the pregnant uterus and to impaired suppressive activity of MDSC. While expression of chemokine receptors and integrins on MDSC was not affected by HIF-1 alpha, myeloid HIF-KO led to increased apoptosis rates of MDSC in the uterus. Myeloid-HIF-KO resulted in increased proportions of non-pregnant animals after positive vaginal plug and increased abortion rates, suggesting that activation of HIF-1 alpha dependent pathways in MDSC are important for maintenance of pregnancy.